epidemiological studies: A/E/C/Se not helpful

[jyb]

In recents years, some studies have questioned the usefulness of anti-oxidants in fruit and vegetables. This is more or less in line with what Ray wrote about caffeine being the only real anti-oxidant in the typical diet. I sometimes wonder about whether that extends to the fat solubles A/E - whether those should be taken long term for maintenance, as opposed to only when needed like Alzheimer's, acne... When Ray writes about them, it's often for a specific purpose rather than for maintenance. I think the question should extend to all supplements - hormones, vitamins, drugs etc: should you take them in times when there's no acute problem? The work below suggests A/E/C and selenium aren't magic as there isn't even a positive on average. No surprise for C and beta carotene. I wish caffeine was included in the study.


http://jama.jamanetwork.com/article.aspx?articleid=205797

Context Antioxidant supplements are used for prevention of several diseases.

Objective To assess the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials.

Data Sources and Trial Selection We searched electronic databases and bibliographies published by October 2005. All randomized trials involving adults comparing beta carotene, vitamin A, vitamin C (ascorbic acid), vitamin E, and selenium either singly or combined vs placebo or vs no intervention were included in our analysis. Randomization, blinding, and follow-up were considered markers of bias in the included trials. The effect of antioxidant supplements on all-cause mortality was analyzed with random-effects meta-analyses and reported as relative risk (RR) with 95% confidence intervals (CIs). Meta-regression was used to assess the effect of covariates across the trials.

Data Extraction We included 68 randomized trials with 232 606 participants (385 publications).

Data Synthesis When all low- and high-bias risk trials of antioxidant supplements were pooled together there was no significant effect on mortality (RR, 1.02; 95% CI, 0.98-1.06). Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.05-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.

Conclusions Treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The potential roles of vitamin C and selenium on mortality need further study.

The study was referenced in a Wiki paragraph on oxidative stress:

http://en.wikipedia.org/wiki/Oxidative_stress

Antioxidants as supplements[edit]
The use of antioxidants to prevent disease is controversial.[38] In a high-risk group like smokers, high doses of synthetic beta carotene increased the rate of lung cancer.[39] In less high-risk groups, the use of vitamin E appears to reduce the risk of heart disease, although more recent evidence may in fact suggest the opposite.[40] In other diseases, such as Alzheimer's, the evidence on vitamin E supplementation is mixed.[41][42] Since dietary sources contain a wider range of carotenoids and vitamin E tocopherols and tocotrienols from whole foods, ex post facto epidemiological studies can have differing conclusions than artificial experiments using isolated compounds. However, AstraZeneca's radical scavenging nitrone drug NXY-059 shows some efficacy in the treatment of stroke.[43]

Oxidative stress (as formulated in Harman's free radical theory of aging) is also thought to contribute to the aging process. While there is good evidence to support this idea in model organisms such as Drosophila melanogaster and Caenorhabditis elegans,[44][45] recent evidence from Michael Ristow's laboratory suggests that oxidative stress may also promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species.[46] This process was previously named mitohormesis or mitochondrial hormesis on a purely hypothetical basis.[47] The situation in mammals is even less clear.[48][49][50] Recent epidemiological findings support the process of mitohormesis, with a 2007 meta-analysis indicating studies with a low risk of bias (randomization, blinding, follow-up) find that some popular antioxidant supplements (Vitamin A, Beta Carotene, and Vitamin E) may increase mortality risk (although studies more prone to bias reported the reverse)

 

[Wilfrid]

The biochemist Nick Lane has also very interesting insides about it:

http://www.nick-lane.net/double-agent%20theory.pdf

 

[jyb]

The biochemist Nick Lane has also very interesting insides about it:

http://www.nick-lane.net/double-agent%20theory.pdf

Seems like he's for a trade-off, hormesis from a mild exposure to anti-oxidants and toxins like found in food, with risks attached to extreme stress but also extreme supplementation. I'd say the spirit of that goes against the intuition Ray gives, although again it's not always comparable because Ray focusses on acute problems, but both agree that studies should focus on the mitochondria and oxidative stress rather than genes.

 

[Wilfrid]

The problem with any " anti-oxydants", including caffeine, is that they can act as pro-oxydants under individual specific health condition.

Take, for example, Ray's article on coffee and caffeine:

"...To talk about caffeine, it’s necessary to talk about uric acid. Uric acid, synthesized in the body, is both a stimulant and a very important antioxidant, and its structure is very similar to that of caffeine. A deficiency of uric acid is a serious problem. Caffeine and uric acid are in the group of chemicals called purines.

Purines (along with pyrimidines) are components of the nucleic acids, DNA and RNA, but they have many other functions. In general, substances related to purines are stimulants, and substances related to pyrimidines are sedatives.

When the basic purine structure is oxidized, it becomes in turn hypoxanthine, xanthine, and uric acid, by the addition of oxygen atoms. When methyl groups (CH3) are added to nitrogens in the purine ring, the molecule becomes less water soluble. Xanthine (an intermediate in purine metabolism) has two oxygen atoms, and when three methyl groups are added, it becomes trimethyl xanthine, or caffeine. With two methyl groups, it is theophylline, which is named for its presence in tea. We have enzyme systems which can add and subtract methyl groups; for example, when babies are given theophylline, they can convert it into caffeine.

We have enzymes that can modify all of the methyl groups and oxygen atoms of caffeine and the other purine derivatives. Caffeine is usually excreted in a modified form, for example as a methylated uric acid.

One of the ways in which uric acid functions as an “antioxidant” is by modifying the activity of the enzyme xanthine oxidase, which in stress can become a dangerous source of free radicals. Caffeine also restrains this enzyme. There are several other ways in which uric acid and caffeine (and a variety of intermediate xanthines) protect against oxidative damage. Coffee drinkers, for example, have been found to have lower levels of cadmium in their kidneys than people who don’t use coffee, and coffee is known to inhibit the absorption of iron by the intestine, helping to prevent iron overload."

However, he didn't mention that uric acid can act, also, as a pro-oxidant substance:

"....In 1998, Schlotte et al. showed that uric acid inhibited LDL oxidation. However, subsequent studies showed that in the case of copper-initiated LDL oxidation uric acid behaves itself as prooxidant. It has been suggested that in this case uric acid enhances LDL oxidation by the reduction of cupric into cuprous ions..." extract ( chapter 29.8) from the book "Oxidation and Antioxidants in Organic Chemistry and Biology" by Evgeny T. Denisov and Igor B. Afanas’ev.